This study combines techniques in genetic epidemiology and molecular genetics to define and characterize inherited breast and breast/ovarian cancer predisposing syndromes. It focuses on two hereditary syndromes: (1) the Li-Fraumeni syndrome, known to be caused by mutations in the tumor suppressor gene p53 at l7p13.1; and (2) a newly defined breast/ovary syndrome which is linked to genetic markers at 17q2l. The California state-mandated Cancer Surveillance Program of Orange County (CSPOC) will be used to identify 500 early onset (<age 50) breast cancer cases and 300 ovarian cancer cases of all ages. The parameters needed to identify families and patients with hereditary breast/ovarian cancer will be estimated by applying segregation analysis to family history data for first- and second-degree relatives. Using these parameters, the odds favoring Mendelian segregation of the breast/ovarian cancer phenotype, and the maximum potential lod score for individual families will be determined. Families with greater than 100:1 odds favoring Mendelian segregation, and with a potential lod score greater than 2.0 will be subjected to more extensive studies, and will be entered into a hereditary cancer registry which is linked to the CSPOC database. Multiple cancer families will also be identifIed from the CSPOC database and entered in the study if they meet ascertainment-adjusted segregation criterion. The p53 gene will be examined for inherited mutations in individual patients and obligate gene carriers from hereditary breast/ovarian cancer families in order to determine the frequency of inherited p53 mutations and to determine the specific p53 cancer-predisposing sequence variation which defines different Li-Fraumeni variants. Forty gene linkage families will be identified and marker typing for l7q2l markers will be undertaken in order to identify families with the breast/ovarian syndrome, and to determine the frequency of the disorder among hereditary families. Genetic-marker development and existing computer software designed for high resolution genetic mapping will be extended to direct the strategies for identifying the 1-2 cM region surrounding the breast/ovarian cancer locus in l7q-linked families. This study will provide the means for identifying a large fraction of the population who are at genetically high risk for breast or ovarian cancer, and for determining the significance of inherited cancer predisposing genes as cancer risk factors in the population. It will help develop therapeutic decisions and cancer prevention measures that meet the specific needs of gene carriers by providing the population and molecular data needed to design clinical management and screening programs. Finally, the study of inherited cancer predisposing-mutations will greatly improve our understanding of cancer etiology and progression.